CA2294924A1 - Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds - Google Patents
Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds Download PDFInfo
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- CA2294924A1 CA2294924A1 CA002294924A CA2294924A CA2294924A1 CA 2294924 A1 CA2294924 A1 CA 2294924A1 CA 002294924 A CA002294924 A CA 002294924A CA 2294924 A CA2294924 A CA 2294924A CA 2294924 A1 CA2294924 A1 CA 2294924A1
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- alkyl
- alpha
- hydrogen
- piperazinyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract 40
- 238000000034 method Methods 0.000 title claims abstract 28
- 208000004756 Respiratory Insufficiency Diseases 0.000 title claims abstract 24
- 206010038678 Respiratory depression Diseases 0.000 title claims abstract 24
- 230000000694 effects Effects 0.000 title claims abstract 9
- 239000000203 mixture Substances 0.000 title claims 3
- 239000000841 delta opiate receptor agonist Substances 0.000 claims abstract 22
- 239000003814 drug Substances 0.000 claims abstract 16
- 229940079593 drug Drugs 0.000 claims abstract 13
- 208000002740 Muscle Rigidity Diseases 0.000 claims abstract 6
- 230000001404 mediated effect Effects 0.000 claims abstract 5
- 239000002756 mu opiate receptor agonist Substances 0.000 claims abstract 5
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 claims abstract 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 85
- 239000001257 hydrogen Substances 0.000 claims 85
- 150000002431 hydrogen Chemical class 0.000 claims 57
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 55
- 229910052799 carbon Inorganic materials 0.000 claims 28
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 25
- 125000003710 aryl alkyl group Chemical group 0.000 claims 25
- 229910052736 halogen Inorganic materials 0.000 claims 24
- 150000002367 halogens Chemical group 0.000 claims 24
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 22
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 20
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims 20
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 20
- 150000002148 esters Chemical class 0.000 claims 20
- 229910052760 oxygen Inorganic materials 0.000 claims 20
- 239000001301 oxygen Substances 0.000 claims 20
- 239000008194 pharmaceutical composition Substances 0.000 claims 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 17
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 16
- 125000000217 alkyl group Chemical group 0.000 claims 16
- 125000000304 alkynyl group Chemical group 0.000 claims 16
- 150000003839 salts Chemical class 0.000 claims 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 15
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 15
- 125000003342 alkenyl group Chemical group 0.000 claims 15
- 125000003118 aryl group Chemical group 0.000 claims 15
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 15
- 229910052757 nitrogen Inorganic materials 0.000 claims 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 13
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 12
- 125000004429 atom Chemical group 0.000 claims 12
- 150000003857 carboxamides Chemical class 0.000 claims 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 10
- 125000001424 substituent group Chemical group 0.000 claims 10
- 229940124530 sulfonamide Drugs 0.000 claims 10
- 150000003456 sulfonamides Chemical class 0.000 claims 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 8
- 150000001721 carbon Chemical group 0.000 claims 8
- 150000003457 sulfones Chemical class 0.000 claims 7
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 claims 6
- 239000005864 Sulphur Substances 0.000 claims 6
- 125000004414 alkyl thio group Chemical group 0.000 claims 6
- 230000000975 bioactive effect Effects 0.000 claims 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 6
- 125000000623 heterocyclic group Chemical group 0.000 claims 6
- 150000003573 thiols Chemical group 0.000 claims 6
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 5
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 5
- 125000002947 alkylene group Chemical group 0.000 claims 5
- 150000001408 amides Chemical class 0.000 claims 5
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 5
- 125000002837 carbocyclic group Chemical group 0.000 claims 5
- 125000004432 carbon atom Chemical group C* 0.000 claims 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 5
- 125000004966 cyanoalkyl group Chemical group 0.000 claims 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 5
- 229960002428 fentanyl Drugs 0.000 claims 5
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims 5
- 239000011737 fluorine Chemical group 0.000 claims 5
- 229910052731 fluorine Chemical group 0.000 claims 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 5
- 239000000863 peptide conjugate Substances 0.000 claims 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- 125000006413 ring segment Chemical group 0.000 claims 5
- 150000003462 sulfoxides Chemical class 0.000 claims 5
- 229910052717 sulfur Inorganic materials 0.000 claims 5
- 239000011593 sulfur Substances 0.000 claims 5
- 150000003568 thioethers Chemical class 0.000 claims 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 3
- 108700040992 Ala(2)- deltorphin I Proteins 0.000 claims 3
- 108700040991 Ala(2)- deltorphin II Proteins 0.000 claims 3
- NUNBRHVOPFWRRG-RCEFDBTISA-N Deltorphin B Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(=O)NCC(N)=O)C(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 NUNBRHVOPFWRRG-RCEFDBTISA-N 0.000 claims 3
- CJAORFIPPWIGPG-QXYJMILXSA-N Deltorphin C Chemical compound C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(=O)NCC(N)=O)C(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 CJAORFIPPWIGPG-QXYJMILXSA-N 0.000 claims 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 3
- 239000002184 metal Substances 0.000 claims 3
- 229940127240 opiate Drugs 0.000 claims 3
- 229940124597 therapeutic agent Drugs 0.000 claims 3
- 210000001519 tissue Anatomy 0.000 claims 3
- 108090000137 Opioid Receptors Proteins 0.000 claims 2
- 102000003840 Opioid Receptors Human genes 0.000 claims 2
- 238000003556 assay Methods 0.000 claims 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 2
- 108020003175 receptors Proteins 0.000 claims 2
- 102000005962 receptors Human genes 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- MCMMCRYPQBNCPH-WMIMKTLMSA-N DPDPE Chemical compound C([C@H](N)C(=O)N[C@@H]1C(C)(C)SSC([C@@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)CNC1=O)C(O)=O)(C)C)C1=CC=C(O)C=C1 MCMMCRYPQBNCPH-WMIMKTLMSA-N 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 claims 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000012216 screening Methods 0.000 claims 1
- LBLDMHBSVIVJPM-YZIHRLCOSA-N 4-[(R)-[(2S,5R)-2,5-dimethyl-4-prop-2-enyl-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1[C@H](C=1C=C(O)C=CC=1)N1[C@@H](C)CN(CC=C)[C@H](C)C1 LBLDMHBSVIVJPM-YZIHRLCOSA-N 0.000 abstract 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 abstract 1
- 229940023861 alfenta Drugs 0.000 abstract 1
- 230000036592 analgesia Effects 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Emergency Medicine (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
A method of reducing, treating or preventing drug-mediated respiratory depression, muscle rigidity, or nausea/vomiting in an animal, incident to the administration to said animal of a mixed delta/mu opioid agonist or a respiratory depression-mediating drug, comprising administering to the animal receiving said drug an effective amount of a delta receptor agonist compound. The figure shows the effect of the positive isomer of the delta agonist BW373U86 on analgesia and respiratory depression induced by the mu agonist, alfenta. The delta agonist compound may comprise a compound of formula (I), wherein the variables of Ar, G, Z, R2, R3, R4, R5, R6 and R7 are herein described in the description.
Claims (45)
1. A method of reducing, treating or preventing drug-mediated respiratory depression in an animal, incident to the administration to said animal of a respiratory depression-mediating drug, comprising administering to the animal receiving said drug an effective amount of a delta receptor agonist compound.
2. A method according to claim 1, wherein the delta agonist also exhibits mu receptor agonist character.
3. A method according to claim 1, wherein said delta receptor agonist is administered with a separate mu receptor agonist compound.
4. A method according to claim 1, wherein the delta agonist is selected from the group consisting of:
(-)-4-((.alpha.R)-.alpha.-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.S)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, deltorphin I;
deltorphin II; and [D-Pen2,D-Pen5)-enkephalin.
(-)-4-((.alpha.R)-.alpha.-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.S)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, deltorphin I;
deltorphin II; and [D-Pen2,D-Pen5)-enkephalin.
5. A method according to claim 1, wherein said delta agonist comprises a compound of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, or R4 is oxygen forming with the carbon atom to which is attached a C=O
group;
R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio;
R6 is phenyl, halogen, NH2 or a para or meta -C(Z)-R8 group, in which Z is oxygen or sulphur;
R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a para or metal group in which R11 and R12 which may the same or different are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, or R4 is oxygen forming with the carbon atom to which is attached a C=O
group;
R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio;
R6 is phenyl, halogen, NH2 or a para or meta -C(Z)-R8 group, in which Z is oxygen or sulphur;
R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a para or metal group in which R11 and R12 which may the same or different are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
6. A method according to claim 1, wherein said delta agonist comprises a compound of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl;
R5 is hydroxy, C1-6 alkoxy, thiol or alkylthio;
R6 is a -C(Z)-Rg group, in which Z is oxygen or sulphur, R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group in which R11 and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl;
R5 is hydroxy, C1-6 alkoxy, thiol or alkylthio;
R6 is a -C(Z)-Rg group, in which Z is oxygen or sulphur, R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group in which R11 and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
7. A method of reducing, treating or preventing drug-mediated respiratory depression in an animal, comprising administering to the animal an effective amount of a compound of the formula:
(I) wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino(carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof.
(I) wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino(carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof.
8. A method according to claim 7, wherein Ar is a 6-member carbocyclic aromatic (benzene) ring and R1 is hydrogen.
9. A method according to claim 7, wherein Y is a carboxamide of the formula CONR9R10.
10. A method according to claim 9, wherein R9 and R10 together form a ring of five or six atoms, thereby forming a pyrrolidinyl or piperidino ring.
11. A method according to claim 9, wherein R9 and R10 are the same or different and are each independently selected from hydrogen, C1 alkyl and C2 alkyl.
12. A method according to claim 8, wherein Y is hydrogen.
13. A method according to claim 8, wherein Y is a sulfone of the formula SO2R8, and R8 is C1-C6 alkyl.
14. A method according to claim 8 wherein G is N, R7 and R2 are each hydrogen, and Z is hydroxyl.
15. A method according to claim 8, wherein R6 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl.
16. A method according to claim 9, wherein R6 is selected from the group consisting of hydrogen, methyl, propyl, allyl and butenyl.
17. A method according to claim 14, wherein R3, R4 and R5 are hydrogen or methyl, where the total number of methyl groups is one or two.
18. A method according to claim 7, wherein R3 and R5 are both methyl, and R4 is hydrogen.
19. A method according to claim 7 wherein the compound is selected from the group consisting of:
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
4-((.alpha.R)-.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
(~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide;
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-methyl-benzamide;
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trimethyl-1-piperazinyl)benzyl)-benzamide;
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S, 5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
(~)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)-phenol;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; or -4-((.alpha.S)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, (~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-4-((.alpha.R*)-.alpha.-((2S*,SR*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxbenzyl)benzamide;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(~)-cis-4-(.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
and pharmaceutically acceptable salts thereof.
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
4-((.alpha.R)-.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
(~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide;
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-methyl-benzamide;
3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trimethyl-1-piperazinyl)benzyl)-benzamide;
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S, 5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
(~)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)-phenol;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; or -4-((.alpha.S)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, (~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-4-((.alpha.R*)-.alpha.-((2S*,SR*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxbenzyl)benzamide;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(~)-cis-4-(.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
and pharmaceutically acceptable salts thereof.
20. A method according to claim 19, wherein the compound is (-)-4-((.alpha.R)-.alpha.-((2R,R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide or a pharmaceutical-ly acceptable salt thereof.
21. A method for screening opioid respiratory depression-suppressing compounds, comprising conducting activity reversal assays of a candidate respiratory depression-suppressing compound in receptor tissue to determine if the candidate respiratory depression-suppressing compound transductionally mediates a respiratory depression effect in the receptor tissue, in response to a respiration-depressing composition, wherein said activity reversal assays are conducted comparatively, in the absence and in the presence of an anti-suppression compound of the formula wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SOR8 where R8 is the same as above;
nitrile;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof, to determine if the activity of the candidate compound is substantially reversed at the tissue site by the presence of the anti-suppression compound of formula (I), thereby indicating the candidate respiratory depression-suppressing compound as possessing potential bioefficacy for supressing respiratory depression effects incident to the use of other therapeutic agents.
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SOR8 where R8 is the same as above;
nitrile;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof, to determine if the activity of the candidate compound is substantially reversed at the tissue site by the presence of the anti-suppression compound of formula (I), thereby indicating the candidate respiratory depression-suppressing compound as possessing potential bioefficacy for supressing respiratory depression effects incident to the use of other therapeutic agents.
22. A method according to claim 21, wherein the anti-suppression compound of formula (I) is selected from the group consisting of:
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; and cis-4-(.alpha.-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; and acceptable salts thereof.
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.S)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; and cis-4-(.alpha.-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; and acceptable salts thereof.
23. A pharmaceutical composition comprising:
(1) an effective amount of a bioactive compound mediating respiratory depression, muscle rigidity, and/or nausea/vomiting as an unwanted side effect thereof;
and (2) a delta receptor agonist.
(1) an effective amount of a bioactive compound mediating respiratory depression, muscle rigidity, and/or nausea/vomiting as an unwanted side effect thereof;
and (2) a delta receptor agonist.
24. A pharmaceutical composition comprising:
(1) an effective amount of a bioactive compound mediating respiratory depression, muscle rigidity, and/or nausea/vomiting as an unwanted side effect thereof;
and (2) a delta receptor agonist selected from the group consisting of:
I. [D-Pen2,D-Pen5]-(enkephalin);
II. deltorphin I;
III. deltorphin II;
IV. delta agonist compounds of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof;
V. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, or R4 is oxygen forming with the carbon atom to which is attached a C=O
group;
R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio;
R6 is phenyl, halogen, NH2 or a para or meta -C(Z)-R8 group, in which Z is oxygen or sulphur;
R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a para or metal group in which R11 and R12 which may the same or different are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R7 is hydrogen, straight or branched C1-8 alkyl or halogen; and VI. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen, R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl;
R5 is hydroxy, C1-6 alkoxy, thiol or alkylthio;
R6 is a -C(Z)-R g group, in which Z is oxygen or sulphur, R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group in which R11 and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
(1) an effective amount of a bioactive compound mediating respiratory depression, muscle rigidity, and/or nausea/vomiting as an unwanted side effect thereof;
and (2) a delta receptor agonist selected from the group consisting of:
I. [D-Pen2,D-Pen5]-(enkephalin);
II. deltorphin I;
III. deltorphin II;
IV. delta agonist compounds of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof;
V. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, or R4 is oxygen forming with the carbon atom to which is attached a C=O
group;
R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio;
R6 is phenyl, halogen, NH2 or a para or meta -C(Z)-R8 group, in which Z is oxygen or sulphur;
R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a para or metal group in which R11 and R12 which may the same or different are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R7 is hydrogen, straight or branched C1-8 alkyl or halogen; and VI. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen, R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl;
R5 is hydroxy, C1-6 alkoxy, thiol or alkylthio;
R6 is a -C(Z)-R g group, in which Z is oxygen or sulphur, R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group in which R11 and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
25. A pharmaceutical composition according to claim 24, in a form suitable for injectable or spinal administration.
26. A pharmaceutical composition comprising:
(1) an effective amount of a bioactive compound mediating respiratory depression; and (2) an effective amount of a compound for reducing, treating or preventing respiratory depression, of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof.
(1) an effective amount of a bioactive compound mediating respiratory depression; and (2) an effective amount of a compound for reducing, treating or preventing respiratory depression, of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof.
27. A pharmaceutical composition according to claim 26, wherein Ar is a 6-member carbocyclic aromatic (benzene) ring and R1 is hydrogen.
28. A pharmaceutical composition according to claim 26, wherein Y is a carboxamide of the formula CONR9R10.
29. A pharmaceutical composition according to claim 26, wherein R9 and R10 together form a ring of five or six atoms, thereby forming a pyrrolidinyl or piperidino ring.
30. A pharmaceutical composition according to claim 26, wherein R9 and R10 are the same or different and are each independently selected from hydrogen, C1 alkyl and C2 alkyl.
31. A pharmaceutical composition according to claim 26, wherein Y is hydrogen.
32. A pharmaceutical composition according to claim 26, wherein Y is a sulfone of the formula SO2R8 and R8 is C1-C6 alkyl.
33. A pharmaceutical composition according to claim 26, wherein G is N, R1 and R2 are each hydrogen, and Z is hydroxyl.
34. A pharmaceutical composition according to claim 26, wherein R6 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl.
35. A pharmaceutical composition according to claim 26, wherein R3, R4 and R5 are hydrogen or methyl, where the total number of methyl groups is one or two.
36. A pharmaceutical composition according to claim 26, wherein R3 and R5 are both methyl, and R4 is hydrogen.
37. A pharmaceutical composition according to claim 26, wherein the compound is selected from the group consisting of:
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
4-((.alpha.R)-.alpha.-(25,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
(~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide;
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-methyl-benzamide;
3-((.alpha.R)-.alpha.-((2S, 5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trimethyl-1-piperazinyl)benzyl)-benzamide;
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S, 5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
(~)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)-phenol;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; or -4-((.alpha.S)-.alpha.-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, (~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-ally 1-2,5-dimethyl-1-piperazinyl)-3-hydroxbenzyl)benzamide;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
(~)-cis-4-(.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
and pharmaceutically acceptable salts thereof.
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
(-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
4-((.alpha.R)-.alpha.-(25,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
(~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide;
N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide;
4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-methyl-benzamide;
3-((.alpha.R)-.alpha.-((2S, 5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trimethyl-1-piperazinyl)benzyl)-benzamide;
(+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S, 5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol;
(~)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)-phenol;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; or -4-((.alpha.S)-.alpha.-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide, (~)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol;
(~)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-ally 1-2,5-dimethyl-1-piperazinyl)-3-hydroxbenzyl)benzamide;
(~)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
(~)-cis-4-(.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide;
and pharmaceutically acceptable salts thereof.
38. A pharmaceutical composition according to claim 37, wherein the compound is (-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide or a pharmaceutically acceptable salt thereof.
39. A pharmaceutical composition according to claim 26, wherein the bioactive compound comprises an opiate compound.
40. A pharmaceutical composition according to claim 26, wherein the bioactive compound comprises an opiate analgesic compound.
41. A pharmaceutical composition according to claim 26, wherein the bioactive compound comprises a mu opiate compound.
42. A method of treating a patient in need thereof with fentanyl while attenuating fentanyl-induced muscle rigidity and fentanyl-induced respiratory depression, comprising administering to the patient a delta agonist compound in an effective amount to attenuate said fentanyl-induced muscle rigidity and fentanyl-induced respiratory depression.
43. A method of treating a patient in need thereof with an opioid receptor therapeutic agent, while attenuating respiratory depression incident to the administration thereof, comprising administering to the patient with said opioid receptor therapeutic agent, a delta agonist compound selected from the group consisting of:
I. [D-Pen2,D-Pen5]-(enkephalin);
II. deltorphin I;
III. deltorphin II;
IV. delta agonist compounds of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof;
V. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, or R4 is oxygen forming with the carbon atom to which is attached a C=O
group;
R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio;
R6 is phenyl, halogen, NH2 or a para or meta -C(Z)-R8 group, in which Z is oxygen or sulphur;
R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a para or metal group in which R11 and R12 which may the same or different are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R7 is hydrogen, straight or branched C1-8 alkyl or halogen; and VI. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl;
R5 is hydroxy, C1-6 alkoxy, thiol or alkylthio;
R6 is a -C(Z)-Rg group, in which Z is oxygen or sulphur, R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group in which R11 and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
I. [D-Pen2,D-Pen5]-(enkephalin);
II. deltorphin I;
III. deltorphin II;
IV. delta agonist compounds of the formula:
wherein:
Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R1, Y is selected from the group consisting of:
hydrogen;
halogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C1-C6 haloalkyl;
C1-C6 alkoxy;
C3-C6 cycloalkoxy;
sulfides of the formula SR8 where R8 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C5-C10 aryl moiety and an C1-C6 alkyl moiety, or C5-C10 aryl;
sulfoxides of the formula SOR8 where R8 is the same as above;
sulfones of the formula SO2R8 where R8 is the same as above;
nitrite;
C1-C6 acyl;
alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 where R8 is the same as above;
carboxylic acid, or an ester, amide, or salt thereof;
aminomethyl of the formula CH2NR9R10 where R9 and R10 may be the same or different, and may be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl, or C5-C10 aryl, or R9 and together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C;
carboxamides of the formula CONR9R10 where R9 and R10 are the same as above, or C2-C30 peptide conjugates thereof; and sulfonamides of the formula SO2NR9R10 where R9 and R10 are the same as above;
Z is selected from the group consisting of:
hydroxyl, and esters thereof;
hydroxymethyl, and esters thereof; and amino, and carboxamides and sulfonamides thereof;
G is carbon or nitrogen;
R1 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R2 is hydrogen, halogen, or C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl;
R3, R4 and R5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R3, R4 or R5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms;
R6 is selected from the group consisting of:
hydrogen;
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
C3-C6 cycloalkyl;
arylalkyl having C5-C10 aryl and C1-C6 alkyl moieties;
alkoxyalkyl having C1-C4 alkoxy and C1-C4 alkyl moieties;
C2-C4 cyanoalkyl;
C2-C4 hydroxyalkyl;
aminocarbonylalkyl having a C1-C4 alkyl moiety; and R12COR13, where R12 is C1-C4 alkylene, and R13 is C1-C4 alkyl or C1-C4 alkoxy; and R7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof;
V. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, or R4 is oxygen forming with the carbon atom to which is attached a C=O
group;
R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio;
R6 is phenyl, halogen, NH2 or a para or meta -C(Z)-R8 group, in which Z is oxygen or sulphur;
R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a para or metal group in which R11 and R12 which may the same or different are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R7 is hydrogen, straight or branched C1-8 alkyl or halogen; and VI. delta agonist compounds of the formula:
in which, R1 and R2, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C3-7 alkyl ring which may be interrupted by oxygen.
R3 and R4, which can be the same or different, are each hydrogen, linear or branched C1-6 alkyl;
R5 is hydroxy, C1-6 alkoxy, thiol or alkylthio;
R6 is a -C(Z)-Rg group, in which Z is oxygen or sulphur, R8 is C1-8-alkyl, C1-8-alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C1-6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group in which R11 and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R7 is hydrogen, straight or branched C1-8 alkyl or halogen.
44. A method of reducing, treating or preventing drug-mediated respiratory depression in an animal, incident to the administration to said animal of a respiratory depression-mediating drug, comprising administering to the animal receiving said drug an effective amount of a compound selected from the group consisting of:
(+)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; and -4-((.alpha.S)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide. and pharmaceutically acceptable salts thereof.
(+)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide;
-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; and -4-((.alpha.S)-.alpha.-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide. and pharmaceutically acceptable salts thereof.
45. A method of reducing, treating or preventing drug-mediated respiratory depression, muscle rigidity, or nausea/vomiting in an animal, incident to the administration to said animal of a respiratory depression-mediating drug, comprising administering to the animal receiving said drug an effective amount of a delta receptor agonist or a mixed delta/mu opioid agonist composition.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/887,312 US5985880A (en) | 1996-06-05 | 1997-07-03 | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
| US08/887,312 | 1997-07-03 | ||
| PCT/US1997/017852 WO1999001033A1 (en) | 1997-07-03 | 1997-10-01 | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
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| CA2294924A1 true CA2294924A1 (en) | 1999-01-14 |
| CA2294924C CA2294924C (en) | 2010-12-21 |
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| CA2294924A Expired - Fee Related CA2294924C (en) | 1997-07-03 | 1997-10-01 | Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds |
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| TR (1) | TR199903324T2 (en) |
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| SE0001207D0 (en) * | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
| US7125718B2 (en) | 2000-05-24 | 2006-10-24 | University Of Maryland Biotechnology Institute | Method for introducing and expressing genes in animal cells, and bacterial blebs for use in same |
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| AU2002341832B2 (en) * | 2001-09-25 | 2008-10-30 | Mount Cook Biosciences, Inc. | An enantiomerically pure diarylmethylpiperazine and methods of using same |
| US7355042B2 (en) * | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
| US8575169B2 (en) | 2001-10-29 | 2013-11-05 | Versi Group, Llc | Method of treating sexual dysfunctions with delta opioid receptor agonist compounds |
| PL371297A1 (en) * | 2001-10-29 | 2005-06-13 | Ardent Pharmaceuticals, Inc. | Method of treating depression with delta receptor agonist compounds |
| US8476280B2 (en) * | 2002-05-09 | 2013-07-02 | Versi Group, Llc | Compositions and methods for combating lower urinary tract dysfunctions with delta opioid receptor agonists |
| SE0203303D0 (en) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| SE0203302D0 (en) * | 2002-11-07 | 2002-11-07 | Astrazeneca Ab | Novel Compounds |
| EP1567490B1 (en) * | 2002-12-04 | 2011-10-05 | Virginia Commonwealth University | Anti-sickling agents |
| US7314880B2 (en) * | 2003-01-02 | 2008-01-01 | Mount Cook Biosciences, Inc. | Cardioprotective delta opioid receptor agonists and methods of using same |
| NZ527142A (en) * | 2003-07-23 | 2006-03-31 | Douglas Pharmaceuticals Ltd | A stable suspension formulation |
| US7119208B2 (en) * | 2003-12-03 | 2006-10-10 | Virginia Commonwealth University | Anti-sickling agents |
| MX2007001240A (en) | 2004-08-02 | 2007-03-23 | Astrazeneca Ab | Diarylmethyl piperazine derivatives, preparations thereof and uses thereof. |
| ES2714198T3 (en) | 2005-03-07 | 2019-05-27 | Univ Chicago | Use of opioid antagonists to attenuate the proliferation and migration of endothelial cells |
| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| US7683168B2 (en) * | 2005-04-14 | 2010-03-23 | Mount Cook Bio Sciences, Inc. | Compositions of novel opioid compounds and method of use thereof |
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| AR092820A1 (en) * | 2012-04-17 | 2015-05-06 | Purdue Pharma Lp | SYSTEMS AND METHODS TO TREAT AN ADVERSE ADVERSE PHARMACODYNAMIC RESPONSE, DOSE UNIT, KIT |
| US9549909B2 (en) | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
| JP6893213B2 (en) | 2015-12-22 | 2021-06-23 | ゾゲニクス インターナショナル リミテッド | Norfenfluramine composition and its preparation method |
| WO2017112701A1 (en) | 2015-12-22 | 2017-06-29 | Zogenix International Limited | Metabolism resistant fenfluramine analogs and methods of using the same |
| RU2746000C2 (en) | 2016-08-24 | 2021-04-05 | Зодженикс Интернэшнл Лимитед | Composition for inhibiting synthesis of 5-ht2b agonist and methods of use thereof |
| WO2018204163A1 (en) * | 2017-04-30 | 2018-11-08 | Versi Group, Llc | An opioid for use to reduce and/or treat drug addiction |
| US10682317B2 (en) | 2017-09-26 | 2020-06-16 | Zogenix International Limited | Ketogenic diet compatible fenfluramine formulation |
| US11571397B2 (en) | 2018-05-11 | 2023-02-07 | Zogenix International Limited | Compositions and methods for treating seizure-induced sudden death |
| WO2019241005A1 (en) | 2018-06-14 | 2019-12-19 | Zogenix International Limited | Compositions and methods for treating respiratory depression with fenfluramine |
| US11612574B2 (en) | 2020-07-17 | 2023-03-28 | Zogenix International Limited | Method of treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) |
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| US2630435A (en) * | 1948-09-09 | 1953-03-03 | Burroughs Wellcome Co | N-benzohydryl-n-methyl piperazines and process of preparing same |
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| EP0287339B1 (en) * | 1987-04-16 | 1994-08-17 | Eli Lilly And Company | Piperidine opioid antagonists |
| US4816586A (en) * | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
| IE902182A1 (en) * | 1989-06-19 | 1991-01-02 | Wellcome Found | Medicaments |
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| IT1270612B (en) * | 1994-07-14 | 1997-05-07 | Smithkline Beecham Farma | MORPHINOID HETEROCYCLE-CONDENSER DERIVATIVES |
| US5753516A (en) * | 1995-02-03 | 1998-05-19 | Heagy; Wyrta E. | Screening method for ligands of the EBI-1 receptor |
| IT1275433B (en) * | 1995-05-19 | 1997-08-07 | Smithkline Beecham Farma | DIARYLDIAMINE DERIVATIVES |
| IT1277597B1 (en) * | 1995-09-15 | 1997-11-11 | Smithkline Beecham Spa | DIARYLALKENYLAMINE DERIVATIVES |
| GB9709972D0 (en) | 1997-05-19 | 1997-07-09 | Pfizer Ltd | Tetrazoles |
| GB9804734D0 (en) | 1998-03-05 | 1998-04-29 | Pfizer Ltd | Compounds |
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1997
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- 1997-10-01 IL IL13360097A patent/IL133600A0/en unknown
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- 1997-10-01 AT AT97910777T patent/ATE259226T1/en not_active IP Right Cessation
- 1997-10-01 AU AU48066/97A patent/AU756120B2/en not_active Ceased
- 1997-10-01 CZ CZ19994694A patent/CZ9904694A3/en unknown
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- 1997-10-01 SI SI9720097A patent/SI20245A/en not_active IP Right Cessation
- 1997-10-01 TR TR1999/03324T patent/TR199903324T2/en unknown
- 1997-10-01 JP JP50859899A patent/JP2002502432A/en active Pending
- 1997-10-01 CA CA2294924A patent/CA2294924C/en not_active Expired - Fee Related
- 1997-10-01 PL PL97337578A patent/PL337578A1/en unknown
- 1997-10-01 WO PCT/US1997/017852 patent/WO1999001033A1/en not_active Application Discontinuation
- 1997-10-01 SK SK1853-99A patent/SK185399A3/en unknown
- 1997-10-01 EP EP97910777A patent/EP1003373B1/en not_active Expired - Lifetime
- 1997-10-01 CN CNB971822719A patent/CN1165308C/en not_active Expired - Fee Related
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1999
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2001
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2005
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| BR9714739A (en) | 2000-07-25 |
| CN1165308C (en) | 2004-09-08 |
| CN1262600A (en) | 2000-08-09 |
| US20020111359A1 (en) | 2002-08-15 |
| SK185399A3 (en) | 2001-08-06 |
| US20080193383A1 (en) | 2008-08-14 |
| IS5309A (en) | 1999-12-17 |
| HUP0003842A3 (en) | 2001-12-28 |
| CA2294924C (en) | 2010-12-21 |
| AU756120B2 (en) | 2003-01-02 |
| US5985880A (en) | 1999-11-16 |
| NZ501817A (en) | 2002-02-01 |
| WO1999001033A1 (en) | 1999-01-14 |
| TW513426B (en) | 2002-12-11 |
| PL337578A1 (en) | 2000-08-28 |
| US20050255151A1 (en) | 2005-11-17 |
| SI20245A (en) | 2000-12-31 |
| IL133600A0 (en) | 2001-04-30 |
| RU2201231C2 (en) | 2003-03-27 |
| TR199903324T2 (en) | 2000-09-21 |
| ATE259226T1 (en) | 2004-02-15 |
| HUP0003842A1 (en) | 2001-04-28 |
| US6300332B1 (en) | 2001-10-09 |
| EP1003373A4 (en) | 2000-09-20 |
| JP2002502432A (en) | 2002-01-22 |
| KR20010014279A (en) | 2001-02-26 |
| EP1003373A1 (en) | 2000-05-31 |
| DE69727593D1 (en) | 2004-03-18 |
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